The present invention relates to novel 6-[2-[2(substituted amino)-3-quinolinyl]ethenyl and ethyl]tetrahydro-4-hydroxypyran-2-ones and/or oxides and the corresponding dihydroxy ring opened acids and esters useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the novel compounds of the present invention are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful as hypolipidemic and hypocholesterolemic agents.
High levels of blood cholesterol and blood lipids are conditions which are involved in the onset of arteriosclerosis. It is well known that inhibitors of HMG-CoA reductase are effective in lowering the level of blood plasma cholesterol, especially low density lipoprotein cholesterol (LDL-C), in man (cf. M. S. Brown and J. L. Goldstein, New England Journal of Medicine, Volume 305, No. 9, pages 515-517 (1981)). It has now been established that lowering LDL-C levels affords protection from coronary heart disease (cf. Journal of the American Medical Association, Volume 251, No. 3, pages 351-374 (1984)).
Moreover, it is known that certain derivatives of mevalonic acid (3,5-dihydroxy-3-methylpentanoic acid) and the corresponding ring-closed lactone form, mevalonolactone, inhibit the biosynthesis of cholesterol (cf. F. M. Singer, et al, Proceedings Society for Experimental Biology and Medicine, Volume 102, pages 370-373 (1959) and F. H. Hulcher, Archives of Biochemistry and Biophysics, Volume 146, pages 422-427 (1971)).
U.S. Pat. Nos. 3,983,140; 4,049,495, and 4,137,322 disclose the fermentative production of a natural product, now called compacting, having an inhibitory effect on cholesterol biosynthesis. Compactin has been shown to have a complex structure which includes a mevalonolactone moiety (A. G. Brown, et al, Journal of Chemical Society Perkin I, pages 1165-1170 (1976)).
U.S. Pat. No. 4,761,419 discloses a series of 6-((substituted)quinolinyl)ethyl)-and ethenyl)tetrahydro-4-hydroxypyran-2-one inhibitors of cholesterol biosynthesis. We have found unexpectedly that incorporation of a 2-substituted amino group in the aforementioned series of compounds results in a series of novel inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase which are useful hypolipidemic and hypocholesterolemic agents.